.
`
`I
`
`1990
`
`USP XXII
`NF XVII
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FoRMULARY
`
`By authority of the United States Pharmacopeial
`Convention, l nc., meeting at Washington, D. C.,
`March 22-24, 1985. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January 1, 1990
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`---
`
`. ----- - .... __
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`
`FRESENIUS EXHIBIT 1068
`Page 1 of 158
`
`

`

`I I
`
`NOTICE AND WARNING
`
`Concerning U. S. Patent or Trademark Rights
`
`The inclusion in the Pharmacopeia or in the National Formulary of a monograph on any
`drug in respect to which patent or trademark rights may exist shall not be deemed, and is
`not intended as, a grant of, or authority to c11.crcisc, any right or privilege protected by such
`patent or trademark. All such rights and privileges are vested in the patent or trademark
`owner, and no other person may exercise the same without express permission, authority, or
`license secured from such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and
`others wishing to use portions of the text should request permission to do so from the
`Secretary of the USPC Board of Trustees.
`
`The United States Phannacopeial Convention, Inc.
`<C> 1989
`12601 Twinbrook Parkway, Rockville, MD 20852
`All rights reserved
`Library of Congress Catalog Card Number 83-640088
`ISSN 0195-7996
`ISBN 0-913595-37-3 (cloth)
`0-913595-38-1 (leather)
`
`Printed by Mack Printing Company, Easton, PA 18042
`
`FRESENIUS EXHIBIT 1068
`Page 2 of 158
`
`

`

`Guide to GENERAL CHAPTERS
`
`(For complete alphabetic list of all general chapters in this Pharmacopeia, sec under "General chapters" io the index.)
`
`General Tests and A~says
`
`General Requirements for Tests and Assays
`(1) Injections ... 14 70
`(I]} USP Reference Standards ... 1472
`
`Apparatus for Tests and Assays
`( 16} Automated Methods of Analysis ... 1473
`(21) Thermometers ... 1477
`{31) Volumetric Apparatus .. . (477
`(4 () Weights and Balances ... 1477
`
`Microbiological Tests
`(51) Antimicrobial Preservatives-Effectiveness ... I 478
`(61) Microbial Limit Tests ... 1479
`(71) Sterility Tests ... 1483
`
`Biological Tests and Assays
`{81) Antibiotics-Microbial Assays ... 1488
`{85) Bacterial Endotoxins Test ... 1493
`(87) Biological Reactivity Tests, In-vitro ... (495
`(88) Biological Reactivity Tests, In-vivo .. . 1497
`(91} Calcium Pantothenate Assay ... 1500
`(101} Depressor Substances Test ... 1502
`{ l I l } Design and Analysis of Biological Assays . . . 1502
`(1 15) Dexpanthenol Assay .. . 1512
`(121) lmu1in Assay ... l 513
`(141} Protein-Biological Adequacy Test ... 1514
`(151} Pyrogen Test ... 1515
`( 161} Transfusion and Infusion Assemblies .. . 1516
`(l 71} Vitamin B12 Activity Assay ... 1516
`
`Chemical Tests aud Assays
`
`IDENTIFICATION TESTS
`{181) Identification-Organic Nitrogenous Bases ... 1518
`(191 ) Identification Tests-Gener.il ... 1518
`(193) Ideotification-Tetracyclil!es . . . !520.
`(201) Thin-layer Chromatographtc IdentificatJon Test ... 1520
`
`LIMIT TESTS
`(211 } Arsenic ... 1520
`(216} Calcium, Potass:iwn, and Sodium ... 1522
`{2ZO Chlorid6 and Sulfate ... 1522
`(224) Dioxane . .. 1522
`(226) 4-Epianhydrotetracycline ... 1523
`(231) Heavy Metals ... 1523
`(241 ) Iron ... 1524
`(251} Lead . .. 1525
`(261) Mercury ... 1526
`(271 } Readily Carbonizablc Substances Test
`(281} Residue on Ignition ... 1527
`{291 } Selenium .. . 1527
`
`. . 1527
`
`1468
`
`OTHER TESTS AND ASSAYS
`(301) Acid-neutralizing Capacity ... 1528
`{3ll) Alginates Assay . .. 1528
`(321) Alkaloidal Drug Assays; Proximate Assays . .. 1529
`{331) Amphetamine Assay ... 1530
`(341} Antunicrobial ~ge~~ntent ... I 530
`(351} Assay for Steroids ..• 1532
`·
`·
`(361) Barii te Assay ... 1532
`in Radiotracer Assay ... 1533
`(371} Co
`{381) Elasto eric Closures for Injections ... l 533
`(391) Epi phrine Assar, ... 1534
`{ 401) Fats\.8Jld Faxed Oils ... 1535
`{411} Folic 'Acid Assay ... 1536
`(421) Hydroxreropoxy Deterinination . . . 1537
`(425) lodometnc Assay-Antibiotics . . . 1538
`(431) Met~oxy De.t~ina~ion ... 1538 " "
`(441} Niacm-c: N.acmamide Assay •.. ,.,3,,
`{451} Nitrite Titration ... 1541
`(461} Nitrogen Determination ... 1542
`(466} Ordinary Impurities ... 1542
`(468} Oxygen Detennination . .. 1543
`(471} Oxygen Flask Combustion ... 1543
`(475) Penicillin G Determination ... 1544
`{481} Riboflavin Assay .•. 1544
`{501) Salts of Organic Nitrogenous Bases ... 1544
`(511} Sing)e-steroid Assay ... 1545
`{521} Sulfonamides ... 1545
`(531} Thiamine Assay ... 1546
`{541} Titrimetry ... 1547
`{551) Alpha Tocophero] Assay .•. 1549
`(561} Vegetable Drugs--Sampling and Methods
`of Analysis ... 1549
`{571} Vitamin A Assay ... 1550
`( 581 } Vitamin D Assay ... 155 I
`(591} Zinc Determination ... 1555
`
`Physical Tests and Determinations
`{601} Aerosols . .. 1556
`{611} Alcohol Determination ... 1557
`(621) Chromatography ... 1558
`{631) Color and Achromicity ... 1568
`{641) Completeness of Solution ... 1569
`(651) Congealing Tempcrafure . . . 1569
`{661} Containers ... 1570 ·
`{671) Containers-Permeation ... 1575
`{691) Cotton ... 1576
`(695} Crystallinity ... 1577
`{701) vis.ultegration ... 1577
`(711) Dissolution ... 1578
`(721) Distilling Range ... 1579
`(724} Drug Release ... 1580
`(726} Electrophoresis ... 1583
`(731} Loss on Drying . . . 1586
`(733} Loss on Ignition ... 1586
`(736} Mass Spectrometry ... 1586
`(741} Melting Range or Temperature .. 1588
`
`FRESENIUS EXHIBIT 1068
`Page 3 of 158
`
`

`

`USPXXIJ
`
`Guide to General Chapters
`
`1469
`
`(7S1} Metal Particles in Ophthalmic Ointments . .. 1S89
`(75S} Minimum Fill ... 1.589
`(761) Nuclear Magnetic Resonance .
`. 1590
`(771) Ophthalmic Ointments ... 1594
`(781) Optical Rotation ... 1595
`(785} Osmolarity ... 1595
`(788} Particulate Matter in Injectiom .. 1.596
`{791) pH ... 1598
`(801} Polarography .. . 1599
`{811} Powder Fmeness ... 1602
`(821} Radioactivity ... 1602
`(831) Refractive Index . .. 1609
`
`(841) Specific Gravity ... 1609
`(851) Spectrophotometry and Light-scattering ..• 1609
`(861) Sutures-Diameter ... 1614
`{871) Sutures-Needle Attachment ... 1614
`{881) Tenaile Strength ... · 1615
`(891} Thermal Analysis ... 1615
`(901} Ultraviolet Absorbance of Citrus Oils ... 1617
`(905) Uniformity of Dosage Units ... 1617
`(911) V~ity ... 1619
`(921) Water Detennmation ... 1619
`(941} X-ray Diffraction ... 1621
`
`General Information
`
`{1001) Antacid Effectiveness ... 1624
`(1035) Biological lodicaton . .. 1625
`{1041) Biologics ... 1627
`.
`(1051) Cleaning Glass Apparatus ... 1627
`{1061) Color-Instrumental Measurement ... 1627
`{l 071) Controlled Substances Act Regulations . . . 1629
`(1076) Federal Food, Drug, and Cosmetic Act ReqwrementJi
`Relating to Drugs for Homan Use ... 1655
`(1077} Good Manu.facturinj Practice for Finished
`Pharmaccutical,s . . . 1671
`.
`{1081) Gel Strength of Gelatin ... 1682
`...
`(1086} Impurities in Official Articles ... 1682
`(1091) Labeling of In.active lngmlien1s ... 1684
`(1101) Medicine Droprer ... 1684
`{ 1111) Microbiologica Attributes of Nonsterile
`PharmaceuticaJ Products . . . 1684
`
`(l 181)
`(1191)
`
`(1121)
`(1141}
`(1151)
`{1171}
`{ 1176}
`
`Nomenclature .. ·. I 685
`Packaging-Child-safety ... 1685
`Pharmaceutical Dosage Forms ... 1688
`Phase-solubility Analysis ... 1697
`Prescription Balances and Volumetric
`Apparatus ... 1699
`Scanrung Electron Microscopy . . . 1700
`Stability Consideratio.m in DISpensing
`Practice. . . 1703
`(121°1} Sterilization and Sterility Assurance of Compendia)
`Articles . . . 1705
`(1221) Teaspoon ... 1710
`.
`( 1225) Validation of Compendia! Methods . . . 1710
`(1231) . Water for Pharmaceutical Purposes ... 1712
`{1241 } W !lter~lid Interactions in Pharmaceutical
`Syatell15 . . . 1713
`
`•
`
`FRESENIUS EXHIBIT 1068
`Page 4 of 158
`
`

`

`GENERAL CHAPTERS
`
`General Tests
`and Assays
`
`General Requirements
`for. Tests and. ~ssays
`
`(1)
`
`INJECTIONS
`
`Ev~ry care shou!d. be ~x.ercised in the preparation of all prod·
`ucts inte!]ded for mJ~tmn, to (lrevent contantination with nu(cid:173)
`~roorgan!sms and foreign matenaJ. _Good P~l'IJ?aceutical prac(cid:173)
`tice requires also thateach final contamer of lnJeCUon be subjected
`indivi~ually to ~ physical inspection, whenever the nature of the
`contamer pemuts, and that every container whose contents show
`~vidence of contamination with visible foreign material be re(cid:173)
`Jected.
`Definitron.-i-In this Pharmacopeia, the sterile preparations for
`parenteral use are grouped into five distinct classes defined as
`follows: (1) medicaments or solutions or emulsions thereof suit•
`able for injection, bearing titles of the form __ Injection· (2)
`dry solids or liquid concentrate.5 containing' no buffers diluents
`or other added substances, and which, upon the addition of 5uit;
`able solvents, yield solutions conforming ia all respects to the
`requirements for Injections, and which are distinguished by titles
`of th~ form, Sterile _·_; (3) preparations the same as those
`d~cnbed under (2) except that tbey contain one or more buffers,
`ddu~nts, or other added substances, and which are distinguished
`by titles o~ the to.rm, --. for l'!jection; ( 4) solids which are
`suspended in a suitable fluid medium and which are not to be
`i~jected intrctvenously or into the spinal canal, distinguished by
`titl!'3 of the fonn, S[e_rile --. Suspe~ion,· and (5) dry solids .
`which, upan_the addition of suitable ve;hicles, yield l)teparations
`conformmg m all respects to the requucments for Sterile Sus(cid:173)
`pen~ions, and which are distinguished by titles of tile form, Stenie
`- - for S uspension.
`1 Pharmacy hulk package is a container of a sterile prepa(cid:173)
`ration for pa!CJ1teral use that contai,ns many single doses. The
`contents arc ~atended for use in a pharmacy admixture program
`and are restricted to the preparation of admixtures for infusion
`or, ~hrough a sterile transfer device, for the filling of empty sterile
`syringes.
`. The clo~ure shall ~e penetrated only one time after constitution
`with a swtable stenle transfer device or dispensing set which
`allows me.a.sured dispensing of the contents. The Pharmacy hulk
`package 1s to be used only in a suitable work area such as a
`1117()
`
`lam in~ fl~ hood (or an equivaJent clean air com,POunding area).
`D~ignation as .a Pharmacy hulk package is limited to prep(cid:173)
`arati.ons from classes l, 2, ?I. 3 as defined above. Pharmacy bulk
`packages, although cc:intauung more than one single dose, are
`exempt from th.e mult1ple-0ose container volume limit of 30 mL
`and the requirement that they contain a ·substance or suitable
`mixture of suhsrances to prevent the growth of microorg;,.nisms.
`Where a container is offered as a Pharmacy hulk package the
`label.shall. (a) s_tat~.prominent;ty "Pharmacy Bulk PackagO-:Not
`for dtrect 10fus1on, (b} contain or refer to information on proper
`techniques t~ h~lp assure. safe use of the product, and (c) bear
`a statement limitmg the tune frame m which the container may
`be used once it has been entered, provided it is held under the
`labeled storage conditions.
`Where used in this Pbarmacopeia, the designation Large-vol(cid:173)
`ume intravel1()US solution applies to a single-dose injection that
`is intended for _il!travenous use and is packaged in containers
`labeled as conta1rung more than l 00 mL. The designation Small(cid:173)
`volume Injection applies to an Injection that is packaged in con(cid:173)
`tainers labeled as containin$ 100 mL or Jess.
`The Pharmaoopeial defimtions for sterile preparations for par·
`enteral use generally do not apply in th.e case of the biologics,
`because of their special nature and licensing requirements (see
`Biologics (1041) ).
`Aqueous Vehicles-The vehicles for aqueous Injections mile!
`the requirements of the Pyrogen Test (ISO or the Bacterial
`Endotoxins Test (85), whi~hever is specified. Water for lnJe<'(cid:173)
`lion generally is used as the vehicle, unless otherwise specified
`in the individual monograph. Sodium chloride may be added m
`am0!1JllS sufficient to render the resulting solution isotonic; and
`Sodium Chloride Injection, or Ringer's Injeclion, may be used
`in whole or in part instead of Waler for Injection unless otherwise
`specified i~ the individual monograph. For condition.~ applying
`to other adJuvants, see Added.~ubstances, in this chapter.
`Other Vehicles-Fixed oils used as vehicles for nonaqueous
`injections are of vegetable origin, are odorless or nearly so, and
`ha~c no odor or taste suggesting rancidity. They meet the ~
`qmrements of thr. t.r.~t for Solid paraffin 11.nifor Mineral Oil, the
`cooling bath being maintained at l 0°, have a Saponification value
`of between 185 and 200 (see Fats and Fixed Oils (401}), have
`an iodine value of between 79 and 128 (see Fats and Fixed Oils
`{ 401} ), and meet the requirements of the following tests:
`Unsaponifiahle Matter-Reflux on a steam bath IO mL oft~
`oil with l 5 rnL of sodium hydroxide solution (1 in 6) and 30 ml,
`of alcohol, with occasional shaking until the mixture becomes
`clear. Transfer the solution to a shallow dish, evaporate the 'u.'.
`coho! on a steam bath, and mix the residue with 100 mL of water·
`a clear solution results.
`
`FRESENIUS EXHIBIT 1068
`Page 5 of 158
`
`

`

`USPXXII
`
`Free Fatty Acfd~'-The free fatty acids in 10 g of oil require
`for neutralization.not more than 2.0 mL of 0.020 N sodium hy-
`· ·
`droxide (see Fats and Fixed Oils {401)).
`Synthetic mono- or diglycerides of fatty acids may be used as
`vehicles, provided they are liquid and remain clear when cooled
`to 10° and have an Iodine value of not more than 140 (see Fats
`and Fixed Oits (401}).
`•
`These and other nonaqueous vehicles may be used, provided
`they are safe in the v?lume of i~jection administ~red, ~d also
`provided they do not interfere with the therapeutic efficacy of
`the.preparation or with its response to prescribed assays and tests.
`Added Substancu-Suitable substances may be added to in(cid:173)
`crease stabiJity o~ uscfliln:ess, unless p~bed in the indivi<i~I
`· monograph, provtded they are harmless m the amounts admtn•
`istered and do not interfere with the therapeutic efficacy or with
`the responses to the specified assays and tests. ~o colon~ ~gent
`may be added, solely. for_ the purpose of co1onng th~ !tms~ed
`{>reparation, to a solution mtended for parenteral adnurustratton
`(see also Added Substances under General Notices, and Anti(cid:173)
`microbial Preservarives-Effectiveness { 5 I)).
`Observe special care in the choice and use of added substances
`in preparations for injection that are administered in a volume
`exceeding 5 mL. The following maximum limits prevail unless
`otherwise directed: for. agents containing mercury and the cat(cid:173)
`ionic surface-active compounds, 0.01 %; for those of the types of
`chlor~butanol, cresol, and phenol, 0.5%; and for sulfur dioxide,
`or an equivalent amount of the sulfite. bisulfite, or metabisulfite
`of potassium or sodium, 0.2%. ·
`· . ·
`A suitable substance or mixture of substances to prevent the
`growth of microorganisms must be added to preparations in(cid:173)
`tended for injection that are packaged in multiplCHlose con(cid:173)
`tainers regardless of the method of sterilization employed, unless
`otherwise directed in the individual mono~aph, or unless the
`active ingredients are themselves antimicrobial. Such substanc~
`are used in contentratibns that will prevent the growth of or kill
`microorganisms in the preparations for injection (see also Anti·
`microbial Preservatives-Effectiveness ( 5 l} and Antimicrobial
`Agents-:-(:onient ( 341} ). Sierilizatio.a processes are employed
`even though such substances are used (sec also Parenteral and
`Topical Preparatwns in th~. section, Added ~ubstances, under
`General Notices and Stenilzation and Sterility Assurance of
`Compendia/ Articles {1211Y). The air in the container may be
`evacuated or be displaced by a chemically inert gas.
`.
`Containers ·ror Injections-Containers, inclu~ the cl05ures,
`for p.reparations for injection do not interact phys1cally or chem(cid:173)
`ically wi~ the.preparations in aay_ rn.anne~ to alter the strength,
`quality, or punty 6eyond the official reqwrements under the or(cid:173)
`dinary or customary con~itio~ of handling, shi_Pment, stora~e,
`sale, and. use. The container 1s made of .matenal that _pemuts
`inspection of the contents. The type of glass preferable for each
`parenteral preparation is usually stated in the individliaJ mono-
`gra/!· definitions of sing{CHlose an<I multiple-dose containers, see
`Contai'ners under General Notices. Containers meet the require-
`.
`ments under Containers (661}.
`.Containers are closed by fusion, or by application of suitable
`closures in such manner as to prevent contamination or loss of
`contents: Closures for multiple,.dose containers permi! the with(cid:173)
`drawar of the contents without removal or destruction of the
`closure. The ciosure permits penetration by a need!~, and, upon
`withdrawal of the needle, at once recloses the container against
`contamination.
`·
`. Coatainers for Sterile Solids-Containers, including the clo(cid:173)
`sures, for dry solids intend_ed for pareote~I ~ do not interact
`physically or chemically with the. preparahon m any. manne~ to
`alter the strength, quabty, or punty beyond the offic1al require(cid:173)
`ments under the ordinary or customary conditions of handling,
`shipment, storage, sale,. and '!Se.
`.
`·
`:
`. .
`. :
`A container for a stenle solid permits the addition of a. suitable
`,iolvent and withdrawal of portions of the resulting solution or
`:ruspension in such manner that the sterility of the product is
`maintained.
`·
`·
`·.
`· .
`Where the Assay in a monograph provides a procedure for
`4ssay preparation in which the total withdrawable contents are
`lo be withdrawn from a singJCHlose container with a hypodennic
`needle and syringe, the contents are to be withdrawn as com(cid:173)
`pletely as possibl~ into a dry hypodermic syringe o_f a rated ca(cid:173)
`pacity not exceeding three tunes the volume to be w1t,hdrawn and
`
`General Requirements / Injections
`
`(1)
`
`1471
`
`fitted with a 21-gauge needle not less than 2.5 cm (l inch) in
`length, care being taken to expel any air bubbles, and discharged
`into a container for dilution and assay.
`Volume in Container-Each container of an Injection is filled
`with a volume in slight exc~s of the labeled "size' or that volu~e
`which is to be withdrawn. The excess volumes recommended in
`the accompanying table are usually sufficient to permit with-
`drawal and administration of the labeled volumes.
`•
`DBTERMINATlQN OF VOLUME OF INJECTION IN CON•
`TAINERS-Select I or more containers if the volume is 10 mL
`or more 3 or more if the volume is more than 3 mL and fess
`than 1o'm.L, or 5 or more if the volume _is 3 mL or J~ss. Take
`up individually the contents of each container selected 111to a. dry
`hypodermic syringe of.a rated capacity not.exceeding three times
`the volume to be measured, and fitted with a 21-gauge needle
`not less than 2.5 cm (1 inch) in length. Expel any air bubbles
`from the syringe and needle? and then dis~harge the con!ents
`of the syringe, without emptymg the needle, into a standardized,
`dry cylinder (graduated to ~ntain rather than to deliver the
`designated volum~) of sue~ stze that the volume to be !lleasured
`occupies at lea.st 40% of its rated volume. Al4':rnattvely, the
`contents of the syringe may be discharged into a dry, tared beaker,
`the volume, in mL, being calculated as the weight, in g, of In(cid:173)
`jection taken divided by its demity. The contents of two or three
`1-mL or 2-mL containers may be pooled for the measurement,
`provided that a separate. dry s:yringe a.ss_embly is used for each
`container. The content of conta10crs holding 10 mL or more may
`be detennined by mearis of opening them and emptying the con(cid:173)
`tents directly into the graduated cylinder or tared beaker.
`
`Labeled Size
`0.5 mL
`l.0mL
`2.0 nu,
`· S.0mL
`10.0 mL
`20.0 mL
`30.0 mL
`50.0 mL
`or more
`
`Recommended Excess Volume
`For Mobile
`For Viscous
`Liquids
`Liquids
`0.10 ml
`0.12 mL
`0.10 mL
`0.15 mL
`0.ZS mL
`iU 5 mL
`0.30 mL
`0.50 m.L
`0.50 mL
`0.70 mL
`0.90 mL
`0.60 rnL
`· 1.20 mL
`0.80 mL
`
`2%
`
`3%
`
`The volume is not less than the labeled volume•in the case of
`containers examined individually or, in the case of 1-mL and 2-
`mL containers, is not less than the sum of the labeled. volumes
`of the containers taken collectively.
`.
`.
`For Injections in multiple--dose containers .lalx::!ed to yield a
`specific number of doses of a stated volume, proceed as ~~cted
`in the foregoing, using the same number of separate syrmges as
`the number of doses specified. The volume is such that each
`.
`syringe delivers not less thllcll the stated dose.
`For lnj«:tions containing oil, warm the containers, if n~essary,
`and thorol!ghlr shake them immediately before removmg the
`contents. Coo to 25° before measuring the volume.
`PMrtblate Midter-AU large-volume lnjc;ctions ~or single-dose
`infusion and those small-volume Injections for which the mono(cid:173)
`graphs ;pecify such requirements, are subject to th~ p~cu~ate
`matter limits set forth under Particulate Matter rn In1ect1ons
`(788). An article packaged as boJh a large-Yolume and a small(cid:173)
`volume Injection meets the reqwrements set forth for Smaf / •
`volume Injedions where the container is labeled as conta4ting
`100 mL or less if the individuaJ monograph includes a test for
`Particulate matter; it meets the requirements set forth for IA,:ge(cid:173)
`vo/ume Injections for Single-dose Infusion w~ere,the container
`io labeled as contau1ing more than 100 mL. lnJections packaged
`a!IP labeled for \!.SP. a1 ir:rigatmg sol•ltiml~ ll,:~ exempt from re(cid:173)
`quirements for Particulate matter.
`Sterility Tests-Preparations for injection meet the require(cid:173)
`ments under Szeri/ity Tests {71).
`LaJ,elm~[NOTE-See definitions of. "label" and "labeling"
`under Preservation, Packa{ing, Storage, and Labeling-Label-
`ing in the General Notlcu.J
`·
`The label state.<. the name of the preparation; in the case of a
`liquid preparatton, the perc.entage content of drug or am_ounl of
`drug in a specified volume; in the case of a dry preparation, the
`
`FRESENIUS EXHIBIT 1068
`Page 6 of 158
`
`

`

`..
`
`1472
`
`(11} USP Reference Standards / General Requirements
`
`USP XX/J
`
`amount of active iog~dient; the route of administration; a state(cid:173)
`ment of storage conditions and an expiration date; the name of
`the manufacturer and distributor; and an identifying lot number.
`The lot number is ca_pable of yielding the complete manufacturing
`history of the specific package, including all manufacturing, fiJI.
`ing, sterilizing. and Jabeling operations.
`.
`Where the individual rn<inograph permits varying concentra•
`tions of active ingredients in the large-volume parenteral, the
`concentration of eayh ingredient named in .the official title is
`stated as if part of the official title, e.g., Dextrose Injection 5%,
`or Dextrose (5%) and Sodium.Chloride (0.2%) Injection.
`The labeling includes the following information, if the complete
`formula is not specified in the individual monograph: (I) In the
`case of a liquid preparation, the percentage content of each in·
`gredient or the amount. of each ingredient in a specified volume,
`except that ingredients added to adjust to a given pH or to make
`the solution isotonic may be declared by name and a statemc.nt
`of their effect; and (2) in the case of a dry preparation cir other
`preparation to which a diluent is intended to be. added before
`use, the amount of each ingr~ient, the composition of recom(cid:173)
`mended diluent(s) [the name(s) alone, if the fonnula is specified
`in the individual monograph~, the amount to be used to attain a
`specific conc.entration of acuve ingredient and the final volume
`of solution so obtained, a brief description of the physical ap(cid:173)
`pearance of the constituted solution, directions for proper storage
`of the constltuted solution, and an expiratiim date limiting the
`period during which the constituted solution may be expected to
`have the required or labeled potency if it has. been stored as
`directed. ·
`· . .
`;
`Containers fodnjections that are intended for use as dialysis,
`hemofiltration, or irrigation solutions and that contain a volume
`of more than· l liter are labeled to indicate that the contents are
`not intended for use by intravenous infusion.
`Injections intended for veterinary use are labeled to that effect.
`The container is so. labeled that a sufficient area of the con(cid:173)
`tainer rclll!lins uncovered for its full length or circumference to
`pennit inspection of the contents.·
`· ·
`Pacbglng and Ston,.ge-Thc volume of Injection in single-dose
`containers provides the amount specified for parenteral admin(cid:173)
`ist?ation at one time and in no case is more than sufficient to
`permit the withdrawal and administration of 1 liter. ·
`Preparations intended for intraspinal, intracisternal, or peri(cid:173)
`dural administration are packaged only in single-dose containers.
`Unless otherwise specified in the individual monograph, no
`muJti{'le-dose cont!l-iner CO?tains a volume of Injection more than
`sufficient to penmt the wtthdrawal of 30 mL.
`Injections packaged for use as irrigation solutions or for hemo•
`filtration or dialysi.s or for parenteral nutrition are exempt from
`the 1-liter re,striction of the foregoing rcquirements relating to
`pack.aging. Containers for Injections packaged for use as hemo(cid:173)
`filtration orirrigation solutions may be designed to empty rapidly
`·
`·
`and may contain a volume of more than l liter.
`Injections labeled for veterinary use are exempt from pack•
`a$ing and storage requirements concerp.ing the limitation to sin(cid:173)
`g)e-<lose containers and the limitation on the volume of multiple(cid:173)
`dose containers.
`
`CONSTITUTED. SOLUTIONS•
`Sterile dosage for-ms from which·constituted solutions are pre(cid:173)
`pared for injection bear titles of the fonn, Sterile __ or _· _
`for Injection. · Since these dosage forms are constituted at the
`time of use by the health-care practitioner, tests and standards
`pertaining to the soiution as constituted for administration aie
`not Included in the individual monographs on sterile dry solids
`or liquid concentrates. However. in the interest of assuring the
`quality of injection prcparatiom as they are actually adminis•
`tcred, the following 11ondestructiYe tests are provided for deni(cid:173)
`onstra:ting the suitability i,f constituted solutiom when they are
`prepared just prior to use.
`·
`·
`·
`Completeness and C1arity of Solutlon--.:.Constitute the soJution
`as directed in the labeling supplied by the manufacturer for the
`steril.c dry dosage form.
`.
`A: The solid.dissolves completely, leaving no visible residue
`.
`as undissolved matter.
`B: The constituted solution is not significantly less. clear
`than an equal volume of the diluent or of Purified Water con•
`· taincd in a similar vessel and examined similarly.
`
`Particulate Matter-Constitute the solution as directed in the
`Iabelmg supplied by the manufacturer for the sterile dry dosage
`form: the solution is essentially free from particles of foreign
`matter that can be observed on visual inspection.
`
`( 11) USP REFERENCE
`STANDARDS ·
`USP Reference Standards are established and released under
`the authority of the USPC Board of Trustees upon recommen•
`dation of the USP Reference Standards Committee, which passes
`on the selection and suitability of each lot. The critical char(cid:173)
`acteristics of each lot of specimen selected for the standard are
`usually detennined independently in thr~. or more laboratories.
`The USP Drug Research and Te..~ting Laboratory (see Preface)
`and the Food and Drug Administration laboratories participate
`in testing almost all new Stal)dards and replacements for existing
`Standards. In addition. laboratories throughout the nation, both
`academic and industrial, participate in the testing.
`. Reference Standards are specifically required in many Phar•
`macopeial assays and tests and are provided solely for such use;
`suitability for other non-official application(s) rests with the pur(cid:173)
`chase. Originally introduced for the biological assays of USP X.
`reference standards are now required for numerous other p~
`cedures as well This reflects the extensive use of modem chro(cid:173)
`matography and spectrophotometry, wb1.ch require measurements
`relaOve to a reference standard. to attain accurate and reprodu•
`cible results.
`.
`. .
`USP Reference Standards are substances selected for their
`high pu;ity, critical characteristics, and suitability for the in·
`tended purpose. ljeterogcneous substances, of natural origin, also
`.are designated "Reference Standards" where needed. Usually
`these arc the counterparts of internat.ional standards.
`Antibiotic reference standards distributed by the USPC have
`been designated by the U.~. Food and Drug Administration as
`identical to t-'1JA working standards under the }il)A certification
`procedures . . USPC distributes both U.S. Reference Standards
`and. USP ~ferenee Standards for antibiotic subs1ances. This
`difference in labeli~ the Standards isin effect only temporarily,
`and cveniually all vials will bear the same title. Where a USP
`Reference. Standard is called for, . the corresponding substance
`labeled as a "U.S. Reference Standard" may be used, and vice
`· versa.·
`·
`,
`.
`·
`Reference Standards currently labeled as ."NF Reference Stan(cid:173)
`. dards" wilJ cventuallf al! be designated and labeled as "USP
`Reference Standards' pursuant to the oonsolidation of USJ> and
`NF within the USPC as of January 2, 1975. Meanwhile, where
`a USP Reference Standard is cal,led for, the. corresponding sub•
`stance la~led as an "NF Reference Standard" may be used.
`Other Ref ercnce Substances
`As a service, the USPC tests and distributes additional au·
`thenticated subs~nces not currently required as USP or NF Ref(cid:173)
`erence Standards: These also are provided under the supervision
`of the USP Reference Standards Committee. These additional
`substances fall into three groups: (1) former USP and NF Ref·
`eretice Standards, not required in the ciment USP or NF but
`for which sufficient demand remains; (Z) FCC Reference Stan·
`dards, specified in the current •edition of the Food Chemic.als
`Codex; and (3) Authentic Substances (AS), which arc highly
`purified sampl~ of chemicals, including s~bstances of abu.se. th~t
`are collaboratively tested and made available as a service pn·
`marily to analytical, clinical, pharmaceutical, and research lab(cid:173)
`oratories.
`The distribution of controlled substances is subject to lhe reg•
`ulations and licensing provisions of tile l>rug .ltnforcement Ad·
`ministration of the Department of Justice.
`As an additional service. the USPC distributes several D-OD(cid:173)
`commercial reagents required in certain USP monographs. These
`reagents are specially prepared for their int.ended use and will '?C
`distributed by USPC only until they become commercially avail·
`able.
`A program to provide international biological standards and
`chemical reference substances is maintained by the World Health
`Organization, an agency of the United Nations. The WHO P~
`gram is concerned with reference materials for antibiotics, hlo--
`
`FRESENIUS EXHIBIT 1068
`Page 7 of 158
`
`

`

`(16)
`
`Apparatus / Automated Methods of Analysis
`logicals, and cbemotherapcu~c ~gents. As a · rule, an In~erna•
`flexibility iii responding to revisions in Retetence Standard usage
`than w.ould exf· iratfon dates. The Catalog . fn the most recent
`tional Standard for a material of natural origin is discontinued
`PhrirmClCOpeia Forum identifies: items that are official in the
`once the substance responsible for its characteristic activity has
`USP Reference Standard~ colJection at· the time. of publication.
`been isolated, identified, and prepared in such form that it can
`be coin_J>)etely characterized by chemical and physical means.
`. Two columns appear in the Catalog to _identify the curr~nt
`official lots. One column identifies the official lot Cllfl"ently being
`The USP Reference Standards Committee collaborates closely
`ship~ed by USPC. In some cases, tlie previous. lot may still be
`with the WHO in order to minimize unavoidable differences in
`considered official. If so, it is identifie<:I in the ~n~ column.
`the actual units ·Of potency, and in some .cases to. share in the
`Ord